Familial Parkinson Disease-associated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein*
| Autor: | A. Anoop, Saumya Dwivedi, Mamata Kombrabail, Samir K. Maji, Dhiman Ghosh, Guruswamy Krishnamoorthy, Shruti Sahay, Ganesh M. Mohite |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Neuron Death
Amyloid animal diseases Mutant Molecular Sequence Data Protein aggregation Wild-Type Biochemistry Polymerase Chain Reaction chemistry.chemical_compound Microscopy Electron Transmission Humans heterocyclic compounds Amino Acid Sequence Amyloid Fibril Formation Molecular Biology Protein secondary structure Alpha-synuclein Tryptophan Fluorescence Sequence Homology Amino Acid Chemistry C-terminus Wild type E46k Mutation Parkinson Disease Cell Biology Synuclein Free-Energy Landscapes Fluorescence Anisotropy Protein Aggregation nervous system diseases Protein Misfolding nervous system Microscopy Fluorescence In-Vitro Protein Structure and Folding Biophysics health occupations Mutagenesis Site-Directed alpha-Synuclein Lewy Bodies Protein folding Time-Resolved Fluorescence Photoinduced Cross-Linking |
| Popis: | Background: Aggregation of -Syn is associated with PD pathogenesis. Results: Despite being natively unfolded, a site-specific structure exists in -Syn that is significantly altered by familial PD-associated E46K, A53T, and A30P mutations. Conclusion: Altered site-specific structure of the PD-associated mutants may attribute to their different aggregation propensity. Significance: This study contributes to understanding the relationship between structure and aggregation of -Syn. Human -synuclein (-Syn) is a natively unstructured protein whose aggregation into amyloid fibrils is associated with Parkinson disease (PD) pathogenesis. Mutations of -Syn, E46K, A53T, and A30P, have been linked to the familial form of PD. In vitro aggregation studies suggest that increased propensity to form non-fibrillar oligomers is the shared property of these familial PD-associated mutants. However, the structural basis of the altered aggregation propensities of these PD-associated mutants is not yet clear. To understand this, we studied the site-specific structural dynamics of wild type (WT) -Syn and its three PD mutants (A53T, E46K, and A30P). Tryptophan (Trp) was substituted at the N terminus, central hydrophobic region, and C terminus of all -Syns. Using various biophysical techniques including time-resolved fluorescence studies, we show that irrespective of similar secondary structure and early oligomerization propensities, familial PD-associated mutations alter the site-specific microenvironment, solvent exposure, and conformational flexibility of the protein. Our results further show that the common structural feature of the three PD-associated mutants is more compact and rigid sites at their N and C termini compared with WT -Syn that may facilitate the formation of a partially folded intermediate that eventually leads to their increased oligomerization propensities. |
| Databáze: | OpenAIRE |
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